Dendritic cells (DC)/Langerhans cells (LC; skin DCs) are sentinels of the immune system. There is growing evidence to suggest that chemokines and their receptors are important determinants of DC/LC trafficking, and that these molecules also play a significant role in T-cell and B-cell function. Over the last two years, significant attention has been focused on CC chemokine receptor 6 (CCR6), CCR7, and CXCR5 and their ligands in DC, and T- and B-cell function, and lymphoid organ homeostasis. However, there is a paucity of information regarding the in vivo role of other chemokine receptors/ligands in these processes. To test the hypothesis that the chemokine system plays an important role in LC/DC and T- and B-cell functions in vivo, we have taken the approach of investigating the loss or gain of immune function in mice lacking one or more of these molecules. In preliminary studies, we found that deficiency of CCR2 but not CCR5 led to distinct defects in DC biology. LC migration to the draining lymph nodes in CCR2-null mice was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen and this was primarily due to a reduction in the CD8alpha+ Thi-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T-cell areas. We propose that these DC defects in conjunction with increased expression of BLC, a B-cell-specific chemokine, may collectively contribute to the striking B-cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. We also found evidence for increased apoptotic activity in the lymphatic channels and infected lymph nodes of CCR2-null but not CCR5-null mice. To test our hypothesis, and to investigate the mechanisms underlying the phenotypes observed in the chemokine receptor gene-deleted mice, we propose four specific aims We will determine the mechanism(s) by which CCR2 influences (1) LC/DC migration, localization and function; (2) APC-effector cell interactions in lymphoid organs; (3) the localization and function of Th1/Th2 inducing DC subsets in the spleen; and (4) we will determine if expression of CCR2 and CCR5 influence Thl and Th2 lymphocyte cell differentiation and homing. These studies will further significantly our understanding of the role of the chemokine system in regulating LC/DC and lymphocyte function, and these insights will offer new opportunities/targets for therapeutic intervention to suppress (transplantation) or stimulate (cancer) the immune response.